Field
Percutaneous transluminal therapy.
Background
Recent studies utilizing autologous mononuclear cells obtained from blood or bone marrow indicate that the introduction (e.g., injection) of these cells into coronary blood vessels (e.g., coronary arteries) will provide a therapeutic benefit to recently infarcted cardiac muscles/vessels as demonstrated by improved cardiac function. In these studies, the injection of a predetermined volume (fluid) of suspended cells is performed via a balloon catheter with an over-sized balloon inflated at a low pressure to avoid additional vessel damage that can lead to stenoses/occlusion. The inflation of the balloon is intended to block coronary blood flow during and for a relatively long period (e.g., about three minutes) after the injection. Following the dwell time, the balloon is deflated for at least a similar time to prevent additional ischemic damage. This procedure is repeated until a desired volume/number of cells has been injected. It is also likely that this procedure may be of benefit to patients suffering from Chronic Heart Failure (CHF).
In the above-described procedure, the coronary blood flow is interrupted to increase the dwell time of the cells in the capillaries and/or the infarcted tissue region. As has been shown by CT and MRI delayed contrast enhancement techniques, infarcted tissue regions contain at least some disrupted/leaky microvasculature that may allow the infused cells to contact tissue in the infarcted region without passing through a capillary wall. Typically, the more time that the cells are in the capillaries and/or the infarcted tissue region, the more opportunities the cells have to adhere to the capillary walls and/or adjacent tissues and transmigrate (travel) into the adjacent tissue where they may multiply and differentiate into tissue types that repair damaged tissues and/or may secrete chemicals that preserve the still living portions of infarcted tissue regions. Transmigration only occurs to a significant extent in the capillaries feeding infarcted or distress tissue regions and in the infarcted or distressed tissue regions. It is believed that the ischemic, distressed and recently infarcted (dead) tissue produces/releases chemicals that signal at least some portion of the mononuclear cells in their vicinity to transmigrate toward/to their location. It is believed that the transmigrated cells differentiate and create new vascular tissue and/or secrete chemicals that preserve the still living tissues (prevent apoptosis) and encourage tissue growth/repair in an infarcted or distressed tissue region.
The above described procedure of introducing mononuclear cells to provide a therapeutic benefit to recently infarcted, ischemic and/or distressed cardiac muscles/vessels is inefficient in at least two ways. First, only a portion of the cells injected can be resident in the capillaries during the occlusion of the arteries. This occurs because the injected suspension of cells must displace most of the blood and fill the volume of the arteries and arterioles distal to the occluding balloon and proximal of the infarcted or distressed region's microvasculature. The cells in this volume will not have the extended time to transmigrate, as they will be washed through the infarcted region once the vessel occlusion is removed by the blood flow.
The second inefficiency is a result of the vascular response to occlusion. Not all of the tissues fed (provided blood) by a recently occluded and now open artery (the one that caused the infarction) will be ischemic, dead, or irreversibly damaged. This is because some of the tissue contains capillaries that are fed by different coronary arteries or by artery branches proximal of the recent occlusion and these capillaries keep the tissue (vessels and muscles) alive, but often in a stunned condition until the occluded site is reopened. It is known that the flow through recently infarcted tissue is abnormal, such that materials injected into their feeding artery will remain resident in infarcted tissues longer (i.e., will wash out slower). This is thought to be a result of the disrupted vessels in the infarcted tissue (the vessel wall cells of the capillaries themselves are dead or damaged and allow leakage directly into the surrounding interstitial spaces). It is also good evidence that the vessel flow resistance of infarcted tissue regions is higher than that of normal tissues. The higher the local flow resistance, the lower the local flow rate and the more time it takes to wash a material into and out from the local tissues and vessels. Also, it is known that as normal tissues become ischemic, their local arterioles become dilated, lowering the local flow resistance and increasing the blood flow through the local tissue (capillaries). Coronary flow reserve (CFR) testing performed at recently occluded sites feeding infarcted tissue regions demonstrates the capacity of at least some of the arterioles to dilate/increase regional blood flow and is good evidence that a recently occluded artery (e.g. by a coronary thrombosis) is feeding at least some normally functioning vasculature and cardiac muscle tissues that can respond to ischemia in the normal way.
Occluding a vessel at a low pressure with a balloon takes a relatively long time. If an inflation fluid is injected at a high pressure to make the inflation more rapid, a potential risk develops of applying a high pressure or oversized balloon to the artery and damaging the artery wall, leading to a restenosis. Efforts to address these problems include making an inflation lumen (and thus the catheter) larger in cross-section (outside diameter (OD)) and/or shorter in length. Larger OD catheters are typically more difficult to position, obstruct blood flow more and lead to more severe insertion site complications. Short catheters restrict the insertion site choices to those not commonly used in a catheter laboratory environment. Attempts to achieve a rapid controlled volume injection require a very compliant and/or over-sized balloon and/or knowledge of the size of the artery and balloon/catheter volume along with specialized injection devices and procedures to avoid vessel injuries. Such balloons, devices and systems are under development but they may be difficult to rapidly deploy and/or control effectively and/or have ease of use issues in the field. As such, currently, the blood flow in an artery will be reduced or occluded for a period of time during the balloon inflation, any testing of the balloon occlusion effectiveness, and the time it takes the physician to lock the inflation in place and to perform the injection. Thus, the normal/more healthy tissues fed by the artery will be, at least to some degree, ischemic and have a lowered flow resistance. This has the effect of routing a greater percentage of a treatment agent (e.g., a cell suspension) flow to the normal/more healthy tissues and not to the distressed/damaged/dead tissues as desired. Additionally, after the injection and the relatively long time of occlusion are completed, the treatment agent resident in the vasculature proximal of the arterioles will be washed by the renewed blood flow through the capillaries. Thus, the treatment agent resident in the vasculature proximal of the arterioles will not only not have the benefit of the occlusion induced longer residence time in the capillaries but, due to that occlusion/ischemic time, will be preferentially routed by the arterioles through the capillaries of the most healthy tissues.